PERSPECTIVE

published: 05 July 2019

doi: 10.3389/fgene.2019.00638

Epigenetic Regulation at the

Interplay Between Gut Microbiota
and Host Metabolism
Joan Miro-Blanch 1,2 and Oscar Yanes 1,2*
1 Metabolomics Platform, IISPV, Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, Spain,
2 Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain

Gut microbiota communities have coevolved for millions of years in a symbiotic

relationship with their mammalian hosts. Elucidating and understanding the molecular
mechanisms by which microbiota interacts with its host and how this contributes to the
homeostasis of the host is crucial. One of these molecular relationships is the so-called
chemical crosstalk between microbiota and host metabolisms, including the poorly
explored epigenetic regulation of host tissues by the metabolic activity of gut microbiota
in response to changes in diet. DNA methylation and histone modifications are epigenetic
marks partly regulated by enzymes such as methylases and acetylases, whose activity
depend on host and microbiota metabolites that act as substrates and cofactors for
these reactions. However, providing a complete mechanistic description of the regulatory
interactions between both metabolisms and the impact on the expression of host genes
Edited by: through an epigenetic modulation, remains elusive. This article presents our perspective
Jane Mellor, on how metabolomic, metagenomic, transcriptomic, and epigenomic data can be used
University of Oxford, United Kingdom
to investigate the “microbiota–nutrient metabolism–epigenetics axis.” We also discuss the
Reviewed by:
implications and opportunities this knowledge may have for basic and applied science,
Tomas J. Ekström,
Karolinska Institute (KI), Sweden such as the impact on the way we structure future research, understand, and prevent
Thomas Roeder, diseases like type 2 diabetes or obesity.
University of Kiel, Germany

*Correspondence: Keywords: microbiota, epigenetics, metabolomics, metabolism, histones, omics

Oscar Yanes
oscar.yanes@urv.cat
CROSSTALK BETWEEN HOST AND GUT MICROBIOTA
Specialty section: METABOLISMS
This article was submitted to
Epigenomics and Epigenetics, The human body co-habit with a diverse community of symbiotic microorganisms and their set
a section of the journal
of genes, collectively known as the microbiome (Ursell et al., 2013). The acquisition of the initial
Frontiers in Genetics
microbiome is a dynamic rather than a static process during early life (Ferretti et al., 2018). A recent
Received: 18 March 2019 estimation of the number of bacterial cells over human cells in our body has reduced the ratio from
Accepted: 18 June 2019
10:1 (Savage, 1977) to a 1.3:1 (Sender et al., 2016a; Sender et al., 2016b). This implies a similar number
Published: 05 July 2019
of bacterial and human cells in and on the human body. However, the human microbiome encodes
Citation:
for at least 100 times more genes than our genome (Qin et al., 2010). Therefore, the corresponding
Miro-Blanch J and Yanes O (2019)
Epigenetic Regulation at the Interplay
higher functionality of bacterial genes is a key aspect to understand existing metabolic interactions
Between Gut Microbiota and Host between the host and its microbiota.
Metabolism. Front. Genet. 10:638. The microbiota helps their hosts to digest dietary fiber; produces some important neurotransmitters
doi: 10.3389/fgene.2019.00638 (Sampson and Mazmanian, 2015; Yano et al., 2015; Strandwitz et al., 2018), hormones, and vitamins

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Miro-Blanch and Yanes
(Kau et al., 2011; Trial et al., 2016); helps in training the host
immune system (Kau et al., 2011; Chu and Mazmanian, 2013);
and protects against pathogens (Watanabe et al., 2017), among
many other functions. However, unbalanced microbiota can also
cause disease. Some common diseases in western societies such
as obesity and type 2 diabetes are associated with shifts in the
relative abundance of gut bacteria composition and functionality,
compared to the ones observed in healthy individuals. The cause
of the microbiota imbalance (dysbiosis) of unhealthy individuals
across age and geography has been mainly correlated with dietary
habits (Turnbaugh et al., 2008; De Filippo et al., 2010; Muegge et al.,
2011; Wu et al., 2011; Arumugam et al., 2011; Menni et al., 2017).
Therefore, the so-called chemical crosstalk between the microbiota
and its host has tangible consequences for the physiological state
of the host (Sharon et al., 2014; Caesar et al., 2015; Ussar et al.,
2016). However, the molecular mechanisms by which microbiota
chemically interacts with host cells and regulate gene expression
remain largely unknown. In this regard, the role that certain host-
microbiota derivate metabolites may exert on epigenetic events at
the DNA, RNA, and histone level needs to be further investigated.
THE “MICROBIOTA–NUTRIENT
METABOLISM–HOST EPIGENETIC” AXIS
Differences in the microbiota or epigenome in two genetically
identical organisms, such as same-sex inbred mice or monozygous
twins, can create differences in susceptibilities to diseases
including  obesity and type 2 diabetes (Ling and Groop, 2009;
Franks and Ling, 2010). As with gut microbiota, new studies have
demonstrated that epigenetic events are highly dynamic, changing
in response to nutrient availability (Bouchard et al., 2010; Hullar
and Fu, 2014) or physical exercise (Laker et al., 2017). DNA
methyltransferases, DNA hydroxylases, histone acetyltransferases,
histone deacetylases, histone methyltransferases, and histone
demethylases are enzymes responsible for adding or removing
these dynamic epigenetic modifications. In this regard,
endogenous metabolites can regulate gene expression through
epigenetic events in host cells (Katada et al., 2012). For instance,
histone deacetylation regulated by sirtuin family deacetylases
is regulated by the NAD+/NADH ratio, acetyl-CoA, O-acetyl-
ADP-ribose, and nicotinamide (Peleg et al., 2016; Ringel et  al.,
2018). Whether gut microbiota metabolism is regulating
the concentration and/or activity of endogenously produced
metabolites by the host remains largely unexplored, and it is only
recently that an increasing number of researchers have started to
investigate this possibility (Krautkramer et al., 2016; Aleksandrova
et al., 2017; Romano et al., 2017). Krautkramer and colleagues
(2016) have demonstrated that microbial colonization regulates
global histone acetylation and methylation in multiple host tissues
in a diet-dependent manner.
Short-chain fatty acids (SCFAs) are exclusively produced by
the microbial fermentation of dietary carbohydrates, and their
abundances are regulated by the composition of the microbiota
(Chen et al., 2007; Cai et al., 2011). Importantly, SCFAs, particularly
butyrate and acetate, produced by the microbiota, inhibit histone
deacetylases (Figure 1) (Maslowski and MacKay, 2011). Increased
Frontiers in Genetics  |  www.frontiersin.org
Gut Microbiota, Host Metabolism and Epigenetics
levels of histone acetylation promote decondensation and relaxation
of chromatin, supporting a more transcriptionally active state of
chromatin (Bolduc et al., 2017).
Alteration of chromatin state is a possible mechanism by
which gut microbiota induces host immune maturation (Cani
et al., 2012; Seeley et al., 2018). Recognition of a “self ” antigen
should not only be limited to mammalian host antigens, but
also symbiotic microbiota antigens forming part of the whole
human ecosystem in a healthy state. The human leukocyte
antigen (HLA) or major histocompatibility complex (MHC)
gene system encodes many antigen-presenting proteins, which
are essential to recognize and distinguish “self ” from “non-self ”
antigens. Colonization of germ-free mice has demonstrated the
capacity of microbiota-specific species to activate MHC class II
genes (Umesaki et al., 1995). However, little is known about the
immunomodulatory effect of microbial metabolites. A poorly
explored possibility is that epigenetically relevant metabolites
such as SCFA, highly influenced by microbiota composition,
would regulate MHC gene expression by coordinating activity of
enzymes that acetylate and methylate histones and DNA allowing
chromatin accessibility (Ting and Trowsdale, 2002).
Regulation of DNA and histone methylation may be driven
by complex microbiota–host metabolism interactions involving
S-adenosyl methionine (SAM), derived from the essential amino
acid methionine through diet (Poirier et al., 2001). Folate plays
an essential role by re-methylating homocysteine to methionine
(Figure 1), thereby ensuring the provision of SAM (Kim, 2005;
Krautkramer et al., 2017). In this regard, enzymes that are depleted in
obese microbiomes are frequently involved in cofactor and vitamin
metabolism (Greenblum et al., 2012), including the production of
cobalamin (vitamin B12), pyridoxal phosphate (the active form of
vitamin B6), tetrahydrofolate, and folate (Arumugam et al., 2011;
Kau et al., 2011; Yatsunenko et al., 2012). Taken together, dysbiosis
of microbiota can influence SAM levels and, as a result, alter the
methylation status of DNA and histones. Whether dysbiosis of
microbiota can alter α-ketoglutarate and succinate levels in specific
peripheral host tissues, and regulate the rate of DNA demethylation,
is a plausible but little explored possibility. Ten-eleven translocation
(TET) enzymes are a key family of DNA and histone demethylases
that use α-ketoglutarate as co-substrate. However, due to the
structural similarity with α-ketoglutarate, Tets are susceptible
to competitive inhibition by fumarate and succinate, causing an
increase in histone and DNA methylation levels (An et al., 2017).
Another modification that could be regulated by microbial
metabolism is histone phosphorylation. In response to a low
ATP/AMP ratio indicative of energy status, the AMP-activated
protein kinase (AMPK) can translocate to chromatin and
phosphorylate histone H2B (Bungard et al., 2010). Changes in
AMPK activity have been reported in obesity, type 2 diabetes,
metabolic syndrome, and cardiovascular disease (Kola et al.,
2008). Interestingly, germ-free mice were resistant to obesity
and insulin resistance that develop after consuming a Western-
style, high-fat, and sugar-rich diet (Bäckhed et al., 2007). The
persistently lean phenotype of germ-free animals was associated
with increased skeletal muscle and liver levels of phosphorylated
AMPK. It is also tempting to speculate that phosphotransferase
systems (PTS) overrepresented in the Western diet microbiomes
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FIGURE 1 | The “microbiota–nutrient metabolism–epigenetics” axis. Most of the key molecules involved in one-carbon metabolism are dietary- and microbiota-
dependent, being susceptible to gut dysbiosis or diet intervention. Folate is the precursor of dihydrofolate (DHF) and tetrahydrofolate (THF), and dietary intake is
the only source for humans. Together with vitamin B12, 5’methy-THF is in charge of remethylating homocysteine (Hcy) to methionine (Met), a crucial step in the
process of transferring a methyl group to DNA or histones through SAM. The ratio of S-adenosyl homocysteine (SAH) to SAM regulates the overall methylation
status of the genome at the DNA or histone level. Vitamins B12, B2, and B6 are key cofactors in the folate cycle that are produced by the microbiota or ingested
through diet. Intermediates of the tricarboxylic acid cycle (TCA) are known to positively or negatively regulate histone methylation. For example, alpha-ketoglutarate
(α-KG) is known to be an essential substrate for jumonji C histone demethylases (jmjC), and levels of succinate and fumarate can inhibit jmjC demethylases.
α-Ketoglutarate is a co-substrate of TET dioxygenases in charge of demethylation processes of histones and DNA. As for jmjC demethylases, increased levels of
fumarate and succinate can inhibit TET enzymes with the consequent increased levels of histone and DNA methylation. Short-chain fatty acids (SCFAs) produced
by the gut microbiota are also known to inhibit or promote histone PTMs. Butyrate and propionate are inhibitors of sirtuins deacetylases enzymes. Acetate from
gut fermentation contributes to the pool of intermediate molecules known to form acetyl-coenzyme A, the major acetyl group donor for histone acetyl transferases
(HATs). Acetate is also known to be an inhibitor of histone deacetylases (HDAC), increasing histone acetylation levels and regulating chromatin accessibility. Whether
levels of FAD/FADH2, NAD/NADH, TCA intermediates, and other host endogenous epigenetically relevant metabolites are modulated by gut microbiota metabolism
needs to be further investigated. DMG, dimethylglycine; ATP, adenosine triphosphate; ADP, adenosine diphosphate; FAD/FADH2, Flavin adenine dinucleotide; NAD+/
NADH, nicotinamide adenine dinucleotide.

(Turnbaugh et al., 2008; Turnbaugh et al., 2009) could have an
impact on this histone modification.
In short, dysbiosis and reduction of the microbiota diversity
can potentially alter the levels of nutrients and metabolites
that can potentially act as regulators of DNA methylation and
histone modifications either by directly inhibiting enzymes that
catalyze the processes, or by altering the availability of substrates
necessary for the enzymatic reactions.
HOLOBIONTS, MULTIFACTORIAL
DISEASES, AND OMIC TECHNOLOGIES
Hosts and their microbiota have a very intimate relationship and
should be considered as a single biological and evolutionary unit,
termed holobiont (Youle et al., 2013; Carrier and Reitzel, 2017;
Groussin et al., 2017; van de Guchte et al., 2018). In this regard,
we could arguably talk about holo–genome, –transcriptome,
–proteome, or –metabolome, referring to the combination of
both, host and host microbiota molecular layers or modules
of information at the DNA, RNA, protein, or metabolite level,
respectively (Figure 2). To investigate the dynamics of the
holobiont ecosystem network, multi-omic approaches bring
unprecedented advantages. Diseases such as obesity and diabetes
are known to be multifactorial, and the collection of several
-omic data (Table 1) from the same holobiont specimen, may
provide a detailed molecular description and new mechanistic
insights of how dietary nutrients and gut microbiota metabolism
can regulate the host phenotype through gene expression and
epigenetic and metabolic regulation.

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Miro-Blanch and Yanes Gut Microbiota, Host Metabolism and Epigenetics

FIGURE 2 | The human holobiont. Representation of few examples of known interactions between different molecular levels within a holobiont. Exercise,
environment, and diet can affect the physiology and molecular interactions between human (host) and its microbiota at the DNA, RNA, protein, or metabolite level.
As an example, fecal host micro RNAs (miRNAs) are used by the host to modulate the composition of its own gut microbiota, interacting at the microbiota RNA and
DNA levels to control microbial growth (Liu et al., 2016). Short-chain fatty acids (SCFAs), products of gut bacterial anaerobic fermentation of dietary fiber, have been
proved to cause changes in histone PTMs in multiple host tissues (Krautkramer et al., 2016). Butyrate is a potent histone deacetylase inhibitor (HDACi), regulating
the transcription levels of genes involved in colorectal tumorigenesis (Hassig et al., 1997). The direct transformation of dietary nutrients (Sharon et al., 2014) and
secondary products of host metabolites such as primary bile acids (Wahlström et al., 2016) evidencies the strong interdependency between host and microbiota.
Folate production by Biffidobacterium spp. is another example of how gut microbiota products can affect epigenetics such as DNA or histone methylation (Paul
et al., 2015). Microbiota diversity shifts, products, or bacterial structural components such as flagellin can cause the activation of the immune system as well as
impact the immune reconstitution after certain diseases or immunotherapy (Manzo and Bhatt, 2015). Immune system maturation and allergic disease development
are other examples of how the host and its microbiome interact (Christmann et al., 2015).

To study a complex metabolic disorder such as familial type
1 diabetes mellitus (T1D), Heintz-Buschart et al. (2016) used
a combination of host genomics and proteomics together with
metagenomics, metatranscriptomics, and metaproteomics
to demonstrate a pronounced family membership effect in
the structuration and functionality of the microbiomes. They
observed a correlation between certain human pancreatic
enzymes and the expression of specific microbial genes involved
in key T1D metabolic transformations. Krautkramer et al. (2016)
used a combination of metabolomic, proteomics of histones,
transcriptomic, and metagenomic techniques in conventional
and germ-free mice, to demonstrate how SCFAs produced by
the microbiota, or supplemented exogenously to germ-free
mice, regulate histone post-translational modifications (PTMs).
Comparing histone PTMs and transcriptional profiles between
conventional, germ-free mice and germ-free mice supplemented
with SCFAs, Krautkramer et al. concluded that SCFAs alone
are partially causative for histone PTMs. In the same direction,
Thaiss et al. (2016) used a combination of metagenomics,
transcriptomics, epigenomics, and metabolomics together with
imaging electron microscopy, to identify a diurnal rhythmicity in
the microbial biogeography, metabolic profile, and metagenomic
functionality as critical orchestrators of host epigenetic marks
and gene expression. Thaiss et al. have demonstrated that host
epigenetic and transcriptional circadian oscillations are partially
dependent on environmental signals such as microbiome

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Miro-Blanch and Yanes Gut Microbiota, Host Metabolism and Epigenetics

TABLE 1 | Popular omic techniques in the fields of epigenomics, metagenomics, metabolomics, and proteomics.

Omics Focus Trait studied Techniques used Reference

Epigenomics DNA modifications 5-methylcytosine WGBS (whole genome bisulfite Seq) (Lister et al., 2009)
RRBS (reduced represented bisulfite Seq) (Xi et al., 2012)
MeDIP-Seq (methylated DNA IP Seq) (Down et al., 2008)
5-hydroxymethylation oxBS-Seq (oxidative bisulfite Seq) (Booth et al., 2012)
5-formylcytosine RedBS-Seq (reduced bisulfite Seq) (Booth et al., 2014)
RNA modifications 6-methyladenosine m6A-Seq (m6A specific methylated IP Seq) (Meyer et al., 2012)
DNA 3D structure DNA structure and ChIP-Seq (chromatin IP Seq) (Barski et al., 2007)
protein interaction ATAC-Seq (assay transposase accessible chromatin Seq) (Buenrostro et al., 2013)
Hi-C (chromatin conformation capture) (Lieberman-Aiden et al., 2009)
DNase-Seq (DNase I hypersensitive sites Seq) (Boyle et al., 2008)
RNA transcripts Transcribed DNA RNA-Seq (mRNA/size/strand Seq) (Mortazavi et al., 2008)
GRO-Seq (global run-on-sequencing Seq) (Core et al., 2008)
NET-Seq (native elongating transcript Seq) (Churchman and Weissman, 2011)
UMI method (unique molecular identifiers) (Kivioja et al., 2012)
Metagenomics Marker gene Hypervariable region 16S gene (16S amplicon PCR/sequencing) (Woese and Fox, 1977)
Whole metagenome Whole genome DNA-Seq (regular DNA Seq) (Tyson et al., 2004)
Metatranscriptome RNA RNA-Seq (regular RNA Seq) (Gilbert et al., 2008)
Metabolomics Targeted Known metabolites QqQ (triple quadrupole) (Lu et al., 2008)
Untargeted profiling Unknown metabolites qTOF-MS (quadrupole time of flight) (Patti et al., 2012)
Orbitrap-MS
NMR (nuclear magnetic resonance) (Brindle et al., 2002)
Proteomics Histones PTMs H2A, H2B, H3, and Bottom-up (Sidoli et al., 2012)
H4 modifications Middle-down
Top-down
MALDI-imaging mass spectrometry (Lahiri et al., 2016)

The integration and combination of these techniques have the potential to reveal more mechanistic insights on how gut microbiota influence epigenetics and gene expression,
ultimately affecting host health. IP, immune precipitation; Seq, sequencing; m6A, 6’methyl adenosine; MS, mass spectrometry; LC, liquid chromatography; GC, gas chromatography;
PTMs, posttranslational modifications; MALDI, Matrix-assisted laser desorption ionization.

metabolite dynamics in the intestines and that peripheral organs
“sense and adapt” to this circadian metabolite rhythms in a
similar manner.
Overall, multi-omic approaches will facilitate the structuration
of future research, improve patient stratification toward a
more personalized care, and open new avenues to evaluate
the effectiveness of functional probiotics, functional foods, or
nutritional interventions aimed at regulating host gene expression
in health and disease.
OPPORTUNITIES FOR BIOMEDICAL AND
CLINICAL RESEARCH
The development and improvement of new technologies and
bioinformatic tools are advancing biomedical research at a fast
pace. Multi-omic experiments are allowing researchers to obtain
mechanistic insights on the human holobiont homeostasis,
improving decision-making for next experiments to be performed.
In a research context, extensive collection of -omic data will allow
integration of information into modulable and controlled models
of microbial communities (Franzosa et al., 2015). However, it is
important to identify confounding factors in longitudinal -omic
studies. Standardization of methods and techniques to reduce
noise and bias in microbiome research will improve how we
translate lab findings into the clinic (Knight et al., 2018).
Using germ-free or gnotobiotic mouse models provide a
framework to manipulate the gut microbial composition in
a controlled manner. These models can be used to study the
chemical crosstalk between host and microbiota by uncovering
specific epigenetic changes in host cells induced by colonization
of specific bacterial strains. Colonizing gnotobiotic mice with
single strains or small bacterial consortia, instead of whole fecal
transplants, might bring more accurate information to understand
specific molecular mechanisms and molecular pathways involved
in the host epigenetic regulations. Microbiota-induced dysbiosis
with antibiotics might provide a useful approach to validate
findings in gnotobiotic models by partially mimicking the effects
of absence of microbiota or a reduction in the microbial diversity.
Interestingly, organoids might also provide a challenging but
very useful in vitro culturing system to study host–microbiota
interactions (Williamson et al., 2018).
In a clinical context, gaining knowledge on the “microbiota–
nutrient metabolism–host epigenetics axis” using multiple
-omic approaches in combination with microbiota modulation
therapies, has the potential to prevent and treat more efficiently
metabolic diseases:
(1)
Fecal microbiota transplantation (FMT): The use of
microbiota modulation therapies such as FMT to treat
recurrent Clostridium difficile infections has been proved
significantly more efficient than a vancomycin treatment
(Petrof and Khoruts, 2012; van Nood et al., 2013). Recently,
the potential of FMT as microbiome modulation technique
for treating metabolic (Kootte et al., 2017) (Gupta et al.,
2016), neurological (Kang et al., 2017), and immunological
disorders (Pamer, 2014) has been tested, improving these
conditions by partially restoring microbiota diversity and

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Miro-Blanch and Yanes
functionality. Assessing long-term host epigenetic effects of
FMT has to be further investigated.
(2) Microbiota as drug target: The unique microbiome
composition of each person is probably responsible for different
susceptibilities to the same nutrient, pollutant, or drug treatment
(Koppel et al., 2017). Microbiota-derived metabolites can enter
the bloodstream and interact with drug treatments, impacting
the efficacy, toxicity, and clearance of the drug. Diagnosing or
treating diseases using microbiota-targeted drugs, probiotics,
and use of bacteriophages or engineered bacteria has recently
re-emerged (Bhat and Kapila, 2017; Landry and Tabor, 2017;
Manrique et al., 2017; Maier et al., 2018).
(3) Nutritional intervention, probiotics, and prebiotics: The acute
consumption of a cocktail of probiotics containing a selection
of five strains of Lactobacillus and five strains of Enterococcus
modulates the microbiome and enhances SCFAs production
in human and mice (Nagpal et al., 2018). The consumption of
some probiotics has proven to be beneficial and ameliorates
stress felt in healthy women (Tillisch Kirsten, 2013), improves
insulin sensitivity (Gomes et al., 2014), protects against
infections (Reid and Burton, 2002), and helps to restore
microbiota after distortion by antibiotics (Langdon et al.,
2016), among other benefits. Promoting SCFAs producing
bacteria in the host gut by a nutritional intervention that
increases fiber consumption (Zhao et al., 2018) may have an
epigenetic effect in the host (Krautkramer et al., 2016).
CONCLUSIONS AND PERSPECTIVE
The study of the “microbiota–nutrient metabolism–host
epigenetic” axis has great potential to reveal the molecular
mechanisms by which gut microbiota composition affects the
expression of genes in their hosts. In a human holobiont context,
this axis is relevant to understand, prevent, diagnose, and treat the
existing epidemic of metabolic disorders such as type 2 diabetes
and obesity. Microbiota is a key player in health outcomes due to
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DATA AVAILABILITY
All datasets analyzed for this study are cited in the manuscript
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AUTHOR CONTRIBUTIONS
JM and OY designed, wrote, revised, and approved the submitted
version of the manuscript.
FUNDING
This work was supported by the European Union’s Horizon 2020
research and innovation program under the Marie Skłodowska-
Curie grant agreement No 675610. OY thanks the following
bodies for funding: Ministerio de Economia y Competitividad
(MINECO) (BFU2017-87958-P) and the Spanish Biomedical
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